Increasing evidences suggest that polymorphisms within the promoter region of the vascular endothelial growth factor (VEGF) gene may elevate the risk for Alzheimer's disease (AD). In Northern Chinese Han, we found three polymorphisms in the VEGF promoter: -2578C/A (rs699947), -2549I/D (rs35569394) and -1154G/A (rs1570360). A strong linkage disequilibrium was detected between -2578C/A and -2549I/D. After adjusting the data by gender, age and the APOEepsilon4 status using logistic regression, the -1154G/G genotype was found to increase the risk for sporadic AD (SAD) by 1.4-folds. In the subgroup of APOEepsilon4 non-carriers, the -1154G allele and -2549D/-1154G haplotype were observed to be significantly higher in the 279 SAD patients than in the 317 healthy individuals. The present study provides the evidence that the -1154G allele and the -2549D/-1154G haplotype may be associated with the development of SAD in the individuals without APOEepsilon4 allele.
"For example, the risk factors for AD and cardiovascular disease are almost identical   and intervention to improve cardiovascular health is the only known effective intervention to prevent AD . Polymorphisms in genes associated with vascular function appear to raise the risk of developing AD , and changes in cortical blood flow have been observed in AD patients . Several studies have shown that cerebrovascular disease such as stroke increases the risk of dementia (particularly AD) by 2- fold among elderly patients   . "
[Show abstract][Hide abstract] ABSTRACT: Oxygen homeostasis is essential for the development and normal physiology of an organism. Hypoxia causes the mitochondrial electron transport chain to generate higher levels of reactive oxygen species resulting in oxidative stress. Hypoxia can be a direct consequence of hypoperfusion, a common vascular component among Alzheimer's disease (AD) risk factors, and may play an important role in AD pathogenesis. Beta-site amyloid-β A4 precursor protein-cleaving enzyme 1 (BACE1) is responsible, with γ-secretase, for cleavage of the amyloid-β protein precursor (AβPP) to produce amyloid-β (Aβ) peptide. A recent study observed that oxidative stress increases BACE1 expression via a regulatory pathway dependent on γ-secretase cleavage of AβPP and this increases Aβ peptide production. Zebrafish embryos represent normal cells in which complex and subtle manipulations of gene activity can be performed to facilitate analysis of genes involved in human disease. Here we identify and describe the expression of bace1, the zebrafish ortholog of human BACE1. We observe that the zebrafish AD-related genes bace1, psen1, psen2, appa, and appb all show increased mRNA levels under hypoxia. A dominant negative form of psen1 putatively blocking γ-secretase activity blocks bace1 upregulation under hypoxia. Hypoxia increases catalase gene mRNA indicating increased oxidative stress but we did not observe increased levels of F2-isoprostanes that indicate peroxidation of arachidonic acid, possibly due to relatively low levels of arachidonic acid in zebrafish. Our results demonstrate that upregulation of PSEN1 & 2, AβPP and the γ-secretase-dependent upregulation of BACE1 is an ancient, conserved, and thus selectively advantageous response to hypoxia/oxidative stress.
[Show abstract][Hide abstract] ABSTRACT: The vascular hypothesis of Alzheimer's disease (AD) has brought the vascular endothelial growth factor (VEGF) into focus. The genomic region including the VEGF gene has been linked to AD and single nucleotide polymorphisms (SNPs) of the VEGF have in previous studies been associated with AD risk. To further evaluate these findings, we genotyped two SNPs in the VEGF gene (rs699947 [-2578]) and rs1570360 [-1154]) by TaqMan Allelic Discrimination in a study sample including AD patients (n = 801) and controls (n = 286). In a subgroup of the population these SNPs were analyzed in relation to APOE epsilon4 genotype, to cerebrospinal fluid biomarkers (T-tau, P-tau, and beta(42)-Amyloid) as well as to neuropathological markers for AD (neurofibrillary tangles and senile plaques). No significant associations with risk for AD or any of the studied biomarkers could be found in this study, thus not supporting VEGF as being a major risk gene for AD.
Neuromolecular medicine 10/2009; 12(3):224-8. DOI:10.1007/s12017-009-8096-8 · 3.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent evidences indicate that polymorphisms within the promoter region of the vascular endothelial growth factor (VEGF) gene may elevate the risk for Alzheimer's disease (AD). To further investigate, we have analyzed association between promoter polymorphisms of the VEGF gene in 93 AD patients and age and sex matched 113 controls from Tunisian population. The distribution of genotype and allele frequencies of the VEGF (-2578C/A) and (-1154G/A) polymorphisms did not differ significantly between AD and control groups (p>0.05). In the subgroup of ApoE varepsilon4 carriers, the -2578A was observed to be significantly higher in the AD patients than in the control individuals. After adjusting the data by gender, age and the ApoE varepsilon4 status using logistic regression, the -2578A allele was found to increase the risk for sporadic AD by 1.7-fold. The present study provides the evidence that the -2578A allele may be associated with the development of AD in the individuals with ApoE varepsilon4 allele. In addition, AD patients carrying the -2578A allele had lower Abeta42 (p=0.029) levels than those without this allele, particularly in subjects with ApoE varepsilon4 allele.
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